bardoxolone methyl (RTA 402) / Kyowa Kirin, Biogen - LARVOL DELTA

Bardoxolone Methyl: A Comprehensive Review of Its Role as a Nrf2 Activator in Anticancer Therapeutic Applications. (PubMed, Pharmaceuticals (Basel)) - "Additionally, bardoxolone methyl modulates mitochondrial function, reduces glycolytic and oxidative phosphorylation capacities, and induces reactive oxygen species (ROS)-mediated stress responses. In this review, we summarize the available literature regarding the studies which investigated the effects of bardoxolone methyl as anticancer agent."

Journal • Review • Brain Cancer • Breast Cancer • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Genito-urinary Cancer • Glioblastoma • Lung Cancer • Oncology • Oral Cancer • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma

CDDO-Me Triggers ROS-Dependent Ferroptosis and Apoptosis in Cervical Cancer via targeting PI3K/Nrf2 pathway. (PubMed, Food Chem Toxicol) - "CDDO-Me induces CC cell lines apoptosis and ferroptosis through the PI3K/Nrf2 signaling pathway, for exerting anti-proliferation effects."

Journal • Cervical Cancer • Oncology • Solid Tumor • GPX4 • NQO1

Bardoxolone methyl inhibits ferroptosis through the Keap1‑Nrf2 pathway in renal tubular epithelial cells. (PubMed, Mol Med Rep) - "Furthermore, BM disrupted the Nrf2‑Keap1 interaction, promoting Nrf2 nuclear translocation. In conclusion, BM may disrupt the Keap1‑Nrf2 interaction in RTECs, upregulate SLC7A11 and mitigate dRib‑induced ferroptosis, thereby presenting a potential therapeutic option to prevent the progression of DKD by protecting RTECs from ferroptosis."

Journal • Chronic Kidney Disease • Diabetic Nephropathy • Nephrology • Renal Disease • ACSL4 • CHAC1 • HMOX1 • PTGS2 • SLC7A11

Basal activation of astrocytic Nrf2 in neuronal culture media: Challenges and implications for neuron-astrocyte modelling. (PubMed, Brain Neurosci Adv) - "Our findings show that while Nrf2 can be effectively activated by the Keap1-Nrf2 protein-protein interaction disruptor 18e, and classical Nrf2 activators dimethylfumarate and CDDO-Me, in human primary cortical astrocyte monocultures, their efficacy is lost in LUHMES neuron-astrocyte co-cultures...As Nrf2 is a key regulator of oxidative damage and neuroinflammation, modelling these common features of neurodegenerative diseases may be confounded by environments that maximally activate basal Nrf2. Our findings thus suggest caution in media selection for neuron-astrocyte co-culture in disease modelling and therapeutic Nrf2 activator discovery, and suggest use of Neurobasal over Advanced DMEM/F12 medias for this purpose."

Journal • CNS Disorders • Inflammation • KEAP1

Hydroxytyrosol induced ferroptosis through Nrf2 signaling pathway in colorectal cancer cells. (PubMed, Sci Rep) - "Additionally, the levels of protein expression of Nrf2 and NQO1 were reversed by two activators of Nrf2, bardoxolone (CDDO) and sulforaphane (SFN). In summary, we provide evidence that HT may induce ferroptosis in colorectal cancer cells. Mechanistically, HT induces ferroptosis via the Nrf2 signaling pathway."

Journal • Colorectal Cancer • Oncology • Solid Tumor • GPX4 • NQO1 • PACERR • PTGS2 • SLC7A11 • TFRC

Keap1-Nrf2 Modulation and SLC7A11 Restoration—Bardoxolone Methyl as a Ferroptosis Inhibitor in Renal Tubular Epithelial Cells (ADA 2025) - "BM inhibits dRib-induced ferroptosis in RTECs by disrupting the association between Nrf2 and Keap1, thereby enhancing Nrf2 nuclear translocation and increasing SLC7A11 gene expression. These findings highlight the therapeutic potential of targeting the Keap1-Nrf2/SLC7A11 axis for DKD treatment without heart failure risk."

Metabolic Disorders • ACSL4 • CHAC1 • KEAP1 • NQO1 • PACERR • PTGS2 • SLC7A11

Cysteine Alkylation in Enzymes and Transcription Factors: A Therapeutic Strategy for Cancer. (PubMed, Cancers (Basel)) - "Synthetic compounds like STAT3-IN-1 and CDDO-Me demonstrated superior binding in most targets, except for CDDO-Me with HIF-1α, suggesting unique structural incompatibilities. Natural products such as zerumbone and umbelliferone displayed moderate activity, while palbociclib highlighted synthetic-drug advantages. These results underscore the importance of ligand-receptor structural complementarity, particularly for HIF-1α's confined binding site, where helenalin's terminal Michael acceptor system proved optimal. The findings advocate for integrating computational and experimental approaches to develop cysteine-targeted therapies, balancing synthetic precision with natural product versatility for context-dependent cancer treatment strategies."

Journal • Review • Oncology • HIF1A • STAT3

Multi-Omics Reveal Antioxidant Effects of Bardoxolone Methyl in the TSUBAKI Study. (PubMed, Kidney360) - "This study demonstrated the first evidence in humans that bardoxolone methyl activates an antioxidant response."

Journal • Diabetic Nephropathy • Nephrology • Renal Disease

Oleanolic acid derivative bardoxolone combats multidrug-resistant Staphylococcus aureus by destroying cell membrane and pyruvate metabolism pathway. (PubMed, J Antimicrob Chemother) - "These findings suggest that bardoxolone holds promise as a candidate drug for treating refractory multidrug-resistant S. aureus infections."

Journal • Infectious Disease • Inflammation • Pneumonia • Respiratory Diseases

Bardoxolone methyl blocks the efflux of Zn2+ by targeting hZnT1 to inhibit the proliferation and metastasis of cervical cancer. (PubMed, Protein Cell) - No abstract available

Journal • Cervical Cancer • Oncology • Solid Tumor

Nrf2-dependent effects of CDDO-Me on bactericidal activity in macrophage infection models. (PubMed, Front Immunol) - "These effects were Nrf2-dependent, as demonstrated in knockout models. The ability of CDDO-Me to regulate oxidative stress, inflammation, and bacterial clearance underscores its therapeutic potential for managing inflammatory and infectious diseases indiabetes and CKD."

Journal • Chronic Kidney Disease • Diabetes • Infectious Disease • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • IL1B • TNFA

Understanding how treatment responses alter the myeloid compartment in BRAF-mutant melanoma (IMMUNOLOGY 2025) - "To investigate this, we employed a tamoxifen-inducible engrafted skin model of melanoma driven by BRAFV600E expression and Pten loss (Braf/Pten model)...We now show that the addition of the synthetic triterpenoid CDDO-Me to the BRAFi PLX4720 arrested resistance and significantly reduced tumor burden...Consistent with this, we identified alterations in myeloid cell recruitment and subset activation during the development of BRAFi resistance using scRNA-seq and flow cytometry. Collectively, these findings indicate that CDDO-Me may impede the development of BRAFi resistance and support its role in novel combination therapies for melanoma.Keywords: Animals Human Rodent; Cells Monocytes/Macrophages; Molecules Cell Surface Molecules; Tissues Skin"

Genetic Disorders • Melanoma • Oncology • Skin Cancer • Solid Tumor • BRAF • PTEN

Bardoxolone methyl suppressed colorectal cancer cells in vitro by inhibiting the PI3K signaling pathway. (PubMed, Sci Rep) - "Importantly, these effects were reversible upon the administration of N-acetylcysteine. Collectively, our findings provide compelling evidence for the potential of CDDO-Me as a promising candidate for the treatment of CRC."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

Bardoxolone Derivatives as Novel Pseudo-Natural Necroptosis Inhibitors by Destabilizing HSP90 Client Proteins. (PubMed, J Med Chem) - "Notably, different from that of CDDO, ZYH-23 could induce destabilizing HSP90 client proteins in a short-term treatment and in a proteasome- and lysosome-independent manner. In summary, the present study provided a series of novel pseudonatural inhibitory candidates for necroptosis-related diseases with a new mechanism."

Journal • Inflammation • CDC37 • HSP90AA1 • RIPK1

Modulation of Lonp1 Activity by Small Compounds. (PubMed, Biomolecules) - "Future research should focus on improving the specificity, bioavailability, and pharmacokinetics of these modulators. Advances in structural biology and drug discovery will enable the development of novel LONP1-targeted therapies, addressing diseases driven by mitochondrial dysfunction and proteostasis imbalance."

Journal • Review • Acute Kidney Injury • Metabolic Disorders • Nephrology • Oncology • Polycystic Ovary Syndrome • Renal Disease • Targeted Protein Degradation • LONP1

Inhibition of renal fibrosis via Nrf2 activators for unilateral ureteral obstruction in a rat model. (PubMed, Pediatr Int) - "Nrf2 activators induced nuclear translocation and activation of Nrf2, resulting in upregulation of ARE-dependent genes. Although the function of Nrf2 in children is often unknown, this study may lead to future progress in oxidation and antioxidant function in children."

Journal • Preclinical • Fibrosis • Immunology • Renal Disease

Senkyunolide I Improves Septicemia-Induced Brain Dysfunction via Regulating Nrf2 and Astrocyte Activity. (PubMed, Biotechnol Appl Biochem) - "Sixty rats were randomly assigned into Sham group, SAE group (Model group), SAE + Sen I group (72 mg/kg, Sen I group), and SAE+ positive control group (RTA 402, Nrf2 receptor agonist, RTA 402 group), with 15 rats in each group...Moreover, Sen I significantly increased the expression of Nrf2 in rat brain tissues. Sen I ameliorates SIBD in rats by regulating the expression of Nrf2 and astrocyte activation."

Journal • CNS Disorders • Infectious Disease • Septic Shock • FAP • GFAP • IL1B • MMP9 • NFE2L2 • OCLN • TNFA

Autocatalytic, Brain Tumor-Targeting Delivery of Bardoxolone Methyl Self-Assembled Nanoparticles for Glioblastoma Treatment. (PubMed, Small Sci) - "Herein, a novel strategy involving the synthesis of p28 peptide-conjugated, lexiscan (LEX)-loaded, bardoxolone methyl (BM) self-assembled nanoparticles, designated as p28-LBM NPs, is introduced. The successful penetration of brain tumors by the p28-LBM NPs after intravenous administration is demonstrated, with BM delivered as part of the NPs significantly inhibiting GBM tumor growth and extending the survival of mice with tumors. In conclusion, the p28-LBM NPs present a promising approach for GBM treatment, with potential for effective and safe clinical applications in the future."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

Systematic Review of Management Strategies for Alport Syndrome: Implications for Male Patients. (PubMed, Health Sci Rep) - "Key interventions examined included bardoxolone methyl, ramipril, and losartan. The protocol for this systematic review is registered in the Open Science Framework (OSF): osf. io/k86ms."

Journal • Review • Genetic Disorders • Nephrology • Otorhinolaryngology • Renal Disease

Oxidative stress and NRF2 signaling in kidney injury. (PubMed, Toxicol Res) - "Clinical trials using bardoxolone methyl, a potent NRF2 activator, have yielded both encouraging and challenging outcomes, illustrating the intricacy of modulating NRF2 in human subjects. In summary, this overview suggests the therapeutic potential of targeting NRF2 in kidney disorders and highlights the necessity for continued research to refine treatment approaches."

Journal • Review • Acute Kidney Injury • Cardiovascular • Chronic Kidney Disease • Diabetic Nephropathy • Fibrosis • Immunology • Nephrology • Renal Disease • Reperfusion Injury

Bardoxolone displays potent activity against triple negative breast cancer by inhibiting the TRIP13/STAT3 circuit. (PubMed, Acta Pharmacol Sin) - "Bardoxolone also exerts great activity to suppress TNBC tumor growth in vivo but does not show toxicity. Therefore, we reveal that the TRIP13/STAT3 circuit promotes TNBC cell proliferation and this circuit is a promising target for the treatment of TNBC."

Journal • Breast Cancer • Chronic Kidney Disease • Nephrology • Oncology • Renal Disease • Solid Tumor • Triple Negative Breast Cancer • STAT3 • TRIP13

Small extracellular vesicles derived from Nrf2-stimulated bone marrow mesenchymal stem cells ameliorated the testis damage and fertility disorder in doxorubicin-treated mice. (PubMed, Reprod Toxicol) - "BMSCs from Wistar rats were treated with Bardoxolone methyl (BaMet) to upregulate Nrf2. In addition, BaMet-sEVs treatment enhanced fertility and increased the number of offspring. This study demonstrated the effectiveness of BaMet-sEVs in mitigating DOX-induced testicular damage."

Journal • Preclinical • NFE2L2

LONP1 INHIBITION PROVOKES IMMUNOGENIC CELL DEATH IN MELANOMA CELLS. (WRMC 2025) - "To inhibit LONP1 protease activity, we utilized CDDO-ME, a synthetic terpenoid. Two compounds, Thapsigargin and Tunicamycin, were used to induce ER stress...Conclusions We conclude that LONP1 inhibition in the presence of ER stress reduces malignant cell immune evasiveness and instead induces ICD. TIMER data analysis suggests a positive correlation between LONP1 inhibition and the strength of the anti-tumor response, resulting in increased CD8+ T cell infiltration and improved patient outcomes, highlighting the potential for LONP1 as a therapeutic target for many cancers."

Immunogenic cell death • Melanoma • Oncology • Solid Tumor • CALR • CD8 • IFNB1 • IL12A • LONP1 • TNFA

TARGETING LONP1 ACTIVITY IN HUMAN MACROPHAGES PROMOTES AN ANTI-TUMOR RESPONSE IN BREAST CANCERS. (WRMC 2025) - "The effects of blocking LONP1 enzymatic activity were assessed using CDDO-Me as a LONP1 inhibitor...Conclusions This study demonstrates that inhibiting LONP1 activity in macrophages exposed to tumor factors reprograms them from an immunosuppressive to a pro-inflammatory phenotype. While the role of LONP1 has been explored in cancer cells in previous studies, our findings highlight its potential as a therapeutic target in macrophages, offering a novel approach to enhance anti-cancer immunity."

Breast Cancer • Infectious Disease • Oncology • Solid Tumor • ANXA5 • CD8 • IFNB1 • IL12A • IL18 • IL1B • IL6 • LONP1 • NLRP3

The Mitochondrial Unfolded Protein Response (UPRmt) Is Upregulated in Acute Myeloid Leukemia (AML) and Inhibiting the UPRmt Protease, LONP1, Leads to Mitochondrial Protein Aggregation and Cell Death Selectively in AML (ASH 2024) - "Genetic depletion and chemical inhibition (Omaveloxolone and Bardoxolone methyl) of LONP1 increased mitochondrial protein aggregation in AML cell lines and primary AML samples with high LONP1 but not normal cells or AML samples with low LONP1 and low mitochondrial protein import. In summary, a subset of AML patients have increased mitochondrial protein import and upregulate UPRmt as a protective response. Targeting UPRmt and the processing of newly imported mitochondrial proteins at the level of LONP1 leads to increased mitochondrial protein aggregation and cell death in AML while sparing normal hematopoietic cells in vitro and in vivo."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • LONP1